The goal of this project is to determine the role of p16, a tumor-suppressor gene in the retinoblastoma cell-cycle regulation pathway, in familial melanoma kindreds. Malignant melanoma is the most lethal of the skin cancers, and unlike most malignancies, often affects younger patients in their third and fourth decades. Several risk factors have been associated with melanoma, including sun exposure, genetic predisposition, total number of nevi present on an individual, and characteristics of nevi. The overall proportion of cutaneous melanoma attributable to genetic predisposition is reported to be about 10- 15%, but evaluation of cancer incidence data from the Utah Population Database suggests that the fraction of melanoma occurring in a familial setting may be as high as 30%. The applicant proposes to re-examine members of Utah melanoma kindreds, first studied 15 years ago at the UUSM, that helped establish the presence of a melanoma susceptibility locus on 9p21 and later confirm the association of p16 mutations with familial melanoma. A five-year mentored program is proposed to investigate the global hypothesis that carriage of a germline p16 mutation results in measurable clinical, histologic, and cellular changes that lead to familial susceptibility to melanoma. This program will incorporate both didactic and research training and will be guided by a research oversight committee composed of four established scientists at the UUSM and the Huntsman Cancer Institute. Three specific aims are proposed. First, clinical differences between carriers and non-carriers of a p16 mutation will be examined in the Familial Melanoma Research Clinic (FMRC) at the Huntsman Cancer Institute. Kindred members studied 15 years ago will be re-examined to measure differences in photodamage, number of nevi, size of nevi, characteristics of nevi, and distribution of nevi among p16 carrier and noncarrier kindred members. Second, I will determine whether p16 mutation carriage results in decreased senescence or apoptosis of nevus cells utilizing B-galactosidase levels and TUNEL staining, respectively. Third, I will determine whether nevi and melanomas from p16 mutation carriers have acquired additional mutations that could lead to increased risk of malignant transformation.